Beyond Band-Aids to cures

Long known as a drug discovery powerhouse, Emory now is finding ways to get those drugs more quickly to market and patients who need them.

In the early 1990s, chemist Dennis Liotta and virologist Raymond Schinazi made drug discovery history with the development of compounds that took HIV from being a certain death sentence to a manageable, chronic disease. The resulting drugs are now routinely used by more than 94 percent of people in the United States and around the world who take medication for HIV/AIDS.

Part of the history-making aspect of the discovery was financial, culminating in a $540 million deal, the largest royalty sale up until that time in higher education. Emory used a portion of its profit to provide initial funding for its 10-year strategic plan, Where Courageous Inquiry Leads. That worked well with requirements of the Bayh-Dole Act that universities use proceeds from such sales to advance scientific research and education.

Since 2005 when its plan launched, Emory has repeatedly hit the mark in drug discovery. A 2011 study in The New England Journal of Medicine put Emory at fourth in the nation for discovering new drugs and vaccines among public-sector research institutions. Emory scientists have received FDA approvals on belatacept -- a new class of less toxic transplant rejection drugs developed by Chris Larsen and Tom Pearsen -- and A. Obizur, for patients with acquired hemophilia, a group of blood-clotting disorders that lead to excessive bleeding that is caused by clotting factor VIII. In developing the drug, Emory hematologist Pete Lollar used a modified form of factor VIII taken from a protein sequence in pigs, which raises less of a red flag to the immune system.

Collectively, drug discovery efforts underway at Emory represent a veritable dictionary of diseases: from those affecting the neurodegenerative and autoimmune systems to infectious and tropical diseases, from cardiovascular disease to previously incurable cancers, from mental health disorders to conditions that don't even yet have a name -- as in Stephen Traynelis's lab, which collaborates with the NIH on its Undiagnosed Diseases Program, as well as pursues other investigations into drugs to treat schizophrenia and stroke.

Not only have Emory faculty excelled in finding potential new drug candidates, but also they've made big strides in the arduous process of getting their discoveries to market. This ability has been enhanced by supporting infrastructure and partners inside and outside the university. For example, the Office of Technology Transfer, led by Todd Sherer, has helped more than 35 drugs and products developed at Emory reach the market -- from a software program that is one of the most widely applied cardiac imaging systems in the world to the only transcranial magnetic stimulation therapy to be approved by the FDA for depression. Also supporting marketability are new business models such as Emory Institute for Drug Development (EIDD) and Drug Innovation Ventures at Emory (DRIVE), partnerships such as the Queensland Emory Development Alliance, and high-tech discovery platforms to support analysis of big data such as the Chemical Biology Discovery Center and the Laboratory for Translational Cell Biology.

Those scientists and supporting activities have allowed Emory and its partners to move faster on drug development than ever before. For example, Schinazi and Liotta launched the start-up Pharmasset based on technologies that they discovered in their HIV drug research, turning that knowledge towards hepatitis C (HCV). Gilead acquired the company on the potential for Pharmasset's HCV drug, Sofosbuvir, and that drug went from the first clinical trials to FDA approval in just five years, according to Schinazi. Prior treatment for HCV was given over the course of 40 weeks, often producing flu-like symptoms and working in only half of those who took it. Clinical trials for the new drug showed that it is 95 to 100 percent effective in curing HCV infection, and it shortens the regimen to eight to 12 weeks with no side effects. Launched in December 2003, this drug has now cured more than 400,000 infected people.

Schinazi believes that the HCV drug investigations show that science is now able to move beyond simply treating patients. "Treatment should be banned from our vocabulary," he says. "The goal should be to cure a medical problem with a pharmaceutical solution, not just put on a Band-Aid to treat it. It is a lot more cost effective to cure than treat a medical condition."

Once it is made more affordable, the new hepatitis C drug promises just that -- with a potential impact far bigger than the HIV/AIDS drug with which Liotta and Schinazi made drug discovery history. According to the World Health Organization (WHO), at least 170 million people worldwide are infected with hepatitis C.

Shortening the long and winding road

Drug development is expensive and time-consuming: developers have to get the potential drug through the so-called "valley of death," the phase when compounds are tested for safety and efficacy in laboratory animals. From potential molecule to FDA approval, a drug might cost $1 billion or more and take up to a decade or more. Investors, foundations, the government, even Big Pharma often decline to provide research funding during the valley phase.

The pharmaceutical industry, driven by profit margins, may be uninterested in pursuing development of drugs for tropical diseases such as West Nile virus, dengue fever, equine encephalitis virus, or the paralyzing Chikungunya -- all targets being pursued at EIDD and DRIVE. "Pharma doesn't see these markets as emerging," Liotta says. "But no therapies exist for many of these single-strand RNA viruses, which account for 80 percent of the virus burden in the world. Because we have the expertise to pull this off, we could make a dramatic impact on global health."

Although universities have the intellectual capital and scientific expertise (in Emory's case in small molecule therapeutics) to find the drugs, universities tend to be less nimble and move more slowly in taking the discovery forward to development. "We've always had the right people," says Liotta. "We didn't always have the right structure."

A remedy for that is DRIVE, a nonprofit organization that adds efficiencies to Emory and removes unintended barriers. Previously Emory licensed promising research to start-up companies and hoped for the best. DRIVE, which functions as a wholly owned subsidiary, allows the university to manage the process longer and potentially reap a bigger reward on investment. It not only has access to Emory's research infrastructure but also the ability to license technologies and then return those resources to the university for further discovery support. It is run by pharmaceutical and biotech business leaders with decades of experience in getting drugs to market. DRIVE also allows Emory to attract government funding in the form of biodefense or preparations for emerging diseases.

Research collaborations with other worldwide partners are furthering the drug development pipeline. For example, the Queensland Emory Drug Discovery Initiative -- a partnership between Emory and the University of Queensland -- aims to speed discovery and development of new drugs for cancer, diabetes, inflammatory disorders, and infectious diseases. (Queensland research led to the development of the cervical cancer vaccine Gardasil.) The initiative, which will emulate DRIVE's model, builds on the Queensland Emory Development Alliance, launched in 2012, and it represents, in the words of Emory President James Wagner, "a common desire to translate our research efforts into positive global transformation."

Because the development of new drugs can be so time-consuming and expensive, Francis Collins, head of the NIH, is encouraging yet another approach to scientific colleagues across the nation: repurposing drugs that are already approved for other uses. One advantage to the approach is saving almost 40 percent in development costs, according to recent estimates. Emory is embracing the charge. Its Office of Technology Transfer has several repurposed drug candidates in its development pipeline: flumazenil (developed for treating overdoses of benzodiazepine) to treat hypersomnia, or excessive sleepiness, rapamycin (developed as an antifungal) to prevent rejection of transplanted organs; osanetant (approved for schizophrenia) to treat anxiety and fear disorders such as post-traumatic stress disorder; and a combination of rapamycin and imatinib (used in patients with chronic myeloid leukemia) for the genetic disorder tuberous sclerosis, TAK-242 (a Japanese drug for treating sepsis) as a non-surgical treatment for ischemic stroke, among other conditions.

Try and try again

Sometimes even drugs that seem the most promising early on run into trouble along the road to development. Take, for example, progesterone for treating traumatic brain injury. Asa G. Candler Professor of Emergency Medicine Don Stein discovered progesterone's neuroprotective properties in basic laboratory research more than two decades ago. The safety and efficacy trials for its use for traumatic brain injury passed without a hitch, but then came a NIH-funded phase 3 clinical trial. ProTECT III, as it was known, was led by Emory and Grady Memorial Hospital ER physician David Wright and involved 49 trauma centers across the United States between July 2009 and November 2013. The trial was cut short when it showed no significant difference in the Glasgow Coma Scores and similar mortality rates of those who received progesterone and those receiving placebo.

However, hope is still alive that the progesterone drug strategy may be effective in stroke and brain tumors. When combined with vitamin D, progesterone helps lessen brain damage in stroke-induced rats, at the same time increasing functional recovery.

A similar scenario played out with the drug arbaclofen, designed to treat fragile X syndrome, the most common inherited form of intellectual disability and a major single-gene cause of autism spectrum disorder. Emory geneticist Stephen Warren had first discovered the gene that causes fragile X, in 1991, and two decades later, Emory was involved in multicenter clinical trials with three pharmaceutical companies to test treatment strategies based on Warren's work. But by spring of 2015, all three trials were closed, one for lack of funding and two for failing to show efficacy.

However, the Simons Foundation Autism Research Initiative (SFARI) reported recently that new mouse studies may support a second chance for the drug -- one showing that arbaclofen corrects abnormalities in the fragile X brain by dampening protein synthesis while ramping up certain proteins to compensate for the drug. That may explain the failure of arbaclofen to improve social skills in the participants with fragile X. The second showed that the drug can ease social deficits and obsessive behaviors in mice that carry features of autism. "Together, the findings from these studies suggest that the drug can achieve real benefit in easing the symptoms of fragile X syndrome and, perhaps, autism," wrote Jessica Wright in the SFARI blog. Funded by the Simons Foundation, SFARI has now purchased the rights to arbaclofen and will revive the trials in people with autism.

In an alternative approach to fragile X syndrome at Emory, scientists Gary Bassell and Christina Gross are developing a drug strategy that targets a form of the enzyme P13 kinase to see if it can improve learning and behavioral flexibility. They previously had shown that one form of P13 kinase is overactivated in the brain of a mouse fragile X model as well as in blood cells from human patients with fragile X syndrome. Their recent work shows that by dialing back the PI3 kinase overactivation, they can alleviate some of the cognitive deficits and behavioral alterations in the mouse model. Bassell, chair of Cell Biology, believes that "further progress in this direction could lead to a clinical trial in fragile X."

Where good basic science can lead

For years, the idea of a universal flu vaccine has been bandied around in basic science laboratories. That took a step closer to reality during the 2009 H1N1 influenza pandemic when a team of Emory scientists led by Emory Vaccine Center Director Rafi Ahmed found something surprising: one region of the influenza protein stayed the same no matter the variant of influenza -- whether A or B, avian, or pandemic. In other words, based on this knowledge, Ahmed explains, it is possible to target these regions of the virus to develop a broadly protective universal vaccine.

"We had no idea we would see this when we went looking," says Ahmed. His NIH-funded research is spawning several collaborations to bring a drug to market to protect immune-compromised people such as those with obesity, pregnant women, and other populations. At this point, the treatment is still too expensive to be made widely available to everyone, but the potential for scaling up the technology is of great interest to the pharmaceutical industry.

On another front, Ahmed's team also is working on drugs and vaccines to prevent and treat Ebola. As soon as the first patients to be treated for Ebola virus arrived at Emory University Hospital's special isolation unit in the fall of 2014, Ahmed began collaborating with the health care team to characterize the virus and study what the immune response to the virus looks like. The four patients treated at Emory have agreed to quarterly blood draws for three years to allow researchers to further their understanding of the Ebola virus.

Currently Ahmed is the principal investigator of a national 10-institution Ebola research effort funded by a nearly $11 million grant from the Defense Advanced Research Projects Agency (DARPA). Researchers will create human monoclonal antibodies targeting Ebola viruses to guide the development of improved therapeutics and vaccines. In addition, the Emory Vaccine Center is part of a government-academic-industry research partnership led by Inovio Pharmaceuticals, Inc. to develop multiple treatment and prevention approaches against Ebola. The national Inovio research team is funded by a two-year contract of up to $45 million from DARPA.

Mark Mulligan at Emory's Hope Clinic will lead one of two clinical trials for a DNA-based vaccine against Ebola in the Inovio effort. In a parallel effort, Baek Kim, director of Emory Children's Center for Drug Discovery, is fast-tracking a program to screen a library of more than 10,000 chemical compounds that can treat viruses at the molecular level to see if one or more of them may show promise to stop Ebola.

Along the way to discovering a new drug, one finding also leads to important implications for another area. For example, Ahmed previously found that T-cells can become exhausted in leading an immune response in chronic infections and that it is possible to restore function back to those T-cells by blocking a molecule known as Programmed Death 1 (PD1). Essentially PD1 puts a brake on the T-cells and blocking it turns them back on. Companies including Bristol Squibb Meyers, Genetech, Merck, Astozenica, and Novartis are all investing in this science with a potential $50 billion market to treat complicated cancers such as non-small-cell lymphoma, melanoma, lung cancer, and bladder cancer.

"We had not worked in cancer drugs before," Ahmed says, "but if you do good science and you're lucky, some good use will come of it."

What cells have to do with it

Beyond the research to deliver cures in the form of drugs is Emory's focus on the power of the body's cells to treat. Marcus Professor of Pediatric Gastroenterology Subra Kugathasan, for example, is leading a clinical trial using the science of personalized cellular therapy to treat adolescents and adults suffering from Crohn's disease. The trial was the first to be launched in partnership with the Emory Personalized Immunotherapy Center (EPIC), directed by hematology-oncology physician Jacques Galipeau.

Symptoms of Crohn's include severe abdominal pain, diarrhea, fever, weight loss, and the inability for a child to properly grow, resulting in bouts of inflammation that may affect the entire digestive tract. Available therapies that suppress the inflammation do not work in everyone, too often leading to bowel resection. The Emory researchers are using a patient's own mesenchymal stromal cells from bone marrow as opposed to cells from an anonymous donor and delivering the cells soon after harvest.

Another clinical trial in partnership with EPIC involves using personalized cellular therapy to treat children and adults suffering from graft-versus-host disease (GVHD). GVHD is a life-threatening complication of bone marrow transplantation in which donor immune lymphocytes attack the organs of the bone marrow transplant recipient. Led by pediatric hematologist-oncologist Muna Qayed, the trial will infuse large doses of the personalized bone marrow cells into bone marrow transplant recipients with the goal of targeting sites of inflammation and potentially reducing GVHD in the intestine, liver, and skin and limiting long-term organ damage.

Arshed Quyyumi, co-director of the Emory Clinical Cardiovascular Research Institute, led one of the largest clinical trials (60 sites, 161 patients) to treat heart attack patients with their own bone marrow cells. The idea behind the treatment was to improve the heart's recovery, and the study improved investigators' knowledge about which cell type and what dose benefitted patients in a high-risk group. Initial results showed that patients who received higher doses of transplanted cells (up to 40 million) had the greatest improvement in cardiac function and statistically significant mortality rates, and the research is now preceding to the final hurdle for showing that it works -- a phase 3 clinical trial.

In addition to the many drug discovery avenues being pursued at Emory, these stem cell treatments are further evidence that scientists are making good on the strategic plan's goal to push the frontiers of science and technology. That goal is evident as well in the Laney Graduate School's Certificate Program in Translational Research. The program is a multidisciplinary program for PhD students, postdocs, and faculty who want to translate basic science knowledge and discovery into applications for treatments to benefit human health.

Furthermore, in the spirit of the university's vision to spread positive transformation in the world, Emory scientists are spreading their knowledge to other parts of the globe. For example, the South Africa Drug Discovery Training Program, established through connections of Liotta with colleagues in South Africa, seeks to transfer expertise in drug discovery to parts of the developing world that need it most.

Liotta envisions the growth of African companies that develop their own therapies for neglected problems in the developing word. With lower operating costs and an ability to attract socially conscious investors, those companies have the potential to once again push scientific frontiers, addressing in particular diseases such as tuberculosis and malaria, to make drug discovery history.